Rare Genetic Lupus Risk Variants and Long-Term Outcomes in Childhood-Onset Systemic Lupus Erythematosus

Objectives Genetic factors strongly contribute to systemic lupus erythematosus (SLE), yet most cases are polygenic. We previously found that 13% of childhood-onset SLE (cSLE) patients carried rare pathogenic variants in monogenic lupus genes, but their impact on outcome is unknown. We compared disease course, organ damage, and healthcare utilization in sequenced cSLE patients with rare SLE-associated variants vs those without these variants. Methods We conducted a cohort study of patients with cSLE followed at The Hospital for Sick Children (2016 – 2024) who underwent whole-exome or whole-genome sequencing. Variants were assessed using our internal pipeline with quality control and depth filters. A predefined gene list (36 monogenic lupus genes) was expanded to include genes with established roles in lupus-relevant immune dysregulation. Rare, potentially pathogenic variants were defined as those with minor allele frequency <1% in gnomAD (Genome Aggregation Database) and predicted deleterious by ≥2 in-silico tools with biologic plausibility. Patients harboring ≥1 qualifying variant were classified as variant-positive. Demographic, clinical, treatment and outcome data were abstracted from the dedicated lupus database, supplemented by chart review. This included ACR/EULAR (American College of Rheumatology/European Alliance of Associations for Rheumatology) classification criteria, SLE manifestations, SLEDAI-2K (Systemic Lupus Erythematosus Disease Activity Index 2000) and SLICC-ACR (Systemic Lupus International Collaborating Clinics) damage index scores prospectively collected over time. We also documented complications such as macrophage activation syndrome (MAS) and hospitalizations. We compared the prevalence of irreversible organ damage or major complications, between ‘variant-positive’ and ‘variant-negative’ patients adjusting for demographic and clinical covariates. Results 151 children and adolescents with cSLE had genome-wide sequencing during the study period; 84% were female, with a median age at diagnosis of 12.8 years (IQR 10.3-15.2). Preliminary review suggests that variant-positive patients are diagnosed at younger age and frequently exhibit classical lupus serology and hypocomplementemia. Identified variants spanned canonical monogenic lupus pathways, including complement genes (eg, C1QA), nucleases and nucleic-acid sensing (eg, DNASE1L3), immune tolerance/lymphoproliferation (eg, CTLA4), and X-linked genes (eg, SAT1). Preliminary review suggests phenotypic heterogeneity across these genetic subgroups with possible differences in treatment intensity and healthcare utilization; full statistical evaluation is ongoing. Conclusion In a diverse cohort of children and adolescents with cSLE, and an expanded list of SLE risk genes, we anticipate at least 13% carry rare pathogenic SLE variants. We expect these patients are more likely to sustain irreversible organ damage compared to those who do not carry rare variants. Our findings will extend our understanding of cSLE and improve prognostication.